Optimal Vitamin D Status as a Strategy to Rescue Cognitive Aging NIA PA-13-303 SUMMARY/ABSTRACT Because the numbers of older adults are increasing dramatically, there is an urgent need to identify interventions that may alleviate the personal/socioeconomic burdens associated with age-related memory impairment. One such potential intervention is treatment with vitamin D. Lower serum vitamin D levels are linked to several age- related disorders including cognitive decline and aging individuals are especially susceptible to vitamin D deficiency. For these reasons and because we previously found that vitamin D can reduce several neurophysiological markers of brain aging, we recently undertook a major vitamin D intervention study in male rats. For 6 months, we fed aging male rats different amounts of vitamin D in an attempt to model serum levels of vitamin D found in humans, ranging from deficient to sufficient. We found that rats with higher serum levels of vitamin D, considered in the ?optimal? range for humans, had superior long term memory, outperforming rats with lower vitamin D on a complex memory task (spatial reversal in the water maze). Additional electrophysiological and gene expression analyses showed that hippocampal synaptic function and multiple synaptic markers were altered with higher serum levels of vitamin D, including gene expression for Nr4a2, an immediate early gene and transcription factor that appears to selectively promote long-term memory. Interestingly, our preliminary results from a separate study show that Nr4a2 is expressed in a sex-dependent manner in the hippocampus. Because women are more than twice as likely to be vitamin D deficient and because the consequences of cognitive aging are greater in women, our goal is to determine whether vitamin D intervention in aging females can offset cognitive decline as it does in males. Therefore, in Aim 1 we directly compare mid-aged male and female F344 rats, treated with diets containing standard or higher vitamin D3, to test the hypothesis that higher serum levels of vitamin D will prevent declining memory function in females as in males. This Aim uses a systems-level approach that includes behavioral testing of multiple forms of memory in the Morris water maze and molecular analyses (gene expression microarrays and immunohistochemistry) to assess processes pertaining to memory. Aim 2 compares males and females on the high vitamin D3 diet to test the novel hypothesis that Nr4a2 is necessary for the cognition enhancing effects of vitamin D. F344 rats will receive intra- hippocampal injections of a viral vector containing shNr4a2 to knockdown Nr4a2 activity. Outcome measures will be the same as in Aim 1. This proposal builds on recent NIH initiatives to investigate sex as a relevant biological variable in order to appropriately tailor therapies/interventions. As the F344 rat is a relevant model of human aging for both sexes, our results also will provide pertinent mechanistic information regarding vitamin D action in the brain. Further, studies on Nr4a2, which selectively promotes long-term memory and appears to be both vitamin D- and sex-dependent, stand to significantly move the field of cognitive aging forward.